ID1 marks the tumorigenesis of pancreatic ductal adenocarcinoma in mouse and human

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease that has an increasing death rate but no effective treatment to now. Although biological and immunological hallmarks of PDAC have been frequently reported recently, early detection and the particularly aggressive biological features are the major challenges remaining unclear. In the current study, we retrieved multiple scRNA-seq datasets and illustrated the genetic programs of PDAC development in genetically modified mouse models. Notably, the transcription levels of Id1 were elevated specifically along with the PDAC development. Pseudotime trajectory analysis revealed that Id1 was closely correlated with the malignancy of PDAC. The gene expression patterns of human PDAC cells were determined by the comparative analysis of the scRNA-seq data on human PDAC and normal pancreas tissues. ID1 levels in human PDAC cancer cells were dramatically increased compared to normal epithelial cells. ID1 deficiency in vitro significantly blunt the invasive tumor-formation related phenotypes. IPA analysis on the differentially expressed genes suggested that EIF2 signaling was the core pathway regulating the development of PDAC. Blocking EFI2 signaling remarkably decreased the expression of ID1 and attenuated the tumor-formation related phenotypes. These observations confirmed that ID1 was regulated by EIF2 signaling and was the critical determinator of PDAC development and progression. This study suggests that ID1 is a potential malignant biomarker of PDAC in both mouse models and human and detecting and targeting ID1 may be a promising strategy to treat or even rescue PDAC.

Bone Morphogenetic Protein (BMP) signaling upregulates expression of ID1 and ID3 in pancreatitis and pancreatic ductal adenocarcinoma

“…The tumorigenic func�on(s) of ID proteins in many cancers is well established 32 . Studies from our lab and others have clearly demonstrated that ID proteins play a pathogenic role in PDAC 6,7,9,10 . We and others have also shown that knockdown of ID1 or ID3 decrease PDAC cell viability 6,10 .…”

“…The tumorigenic function of ID proteins is well established in many cancers 32,33 . In PDAC, studies from our lab and others have clearly demonstrated that ID proteins play a pathogenic role and that knockdown of ID1 or ID3 decreases PDAC tumorigenicity 6,7,9,10 . Our previous work showed that ID1 and ID3 bind to and inhibit the activity of the bHLH transcription factor E47, a splice variant of the E2A / TCF3 gene.…”

“…Importantly, we found that restoring E47 activity in PDAC induced quiescence and expression of acinar cell differentiation markers in vitro and in vivo 7,25 . Given the increasing interest in IDs in PDAC, we investigated upstream signals that might control expression of the ID genes 9,10,29 . BMP signaling was of particular interest as it’s known in many diverse biological processes to induce expression of ID1 and ID3 34 .…”

“…Our independent analysis of human scRNA-seq datasets 19 from normal pancreas and PDAC also demonstrated significant upregulation of ID1 expression specifically in the ductal cell type 2 population. Subsequent trajectory analysis of the mouse PDAC GEMM datasets revealed that expression of Id1 was particularly elevated as malignancy progressed from the early-stage epithelial ductal cell type 1 population to the later-stage ductal cell type 2 population 9 . The same authors analyzed a human scRNA-seq dataset comparing normal pancreas to PDAC and identified ID1 as the top upregulated transcription factor specifically in cancer cells and suggested a role for ID1 in EMT 9 .…”

Smad4and TGF-β1 dependent gene expression biomarkers in conditional intestinal adenoma, organoids and colorectal cancer

“…Later Id1 repression is also thought to be pSmad3 dependent through activation of ATF3 , that then represses Id1 expression 50 . Id1 over-expression in pancreatic ductal adenocarcinoma in mouse and human is associated with more invasive and undifferentiated cells, a mechanism proposed to be dependent on EIF2 signalling 51 and independent of the TGF-β pathway 52 . Here, we found that SMAD4 mutation in CRC patients was associated with low ID1 mRNA expression and poor survival whereas this association has been also been conflicting 53 .…”